Genetics of Nonsyndromic Congenital Hearing Loss

Review ArticleGenetics of Nonsyndromic Congenital Hearing Loss

Oguz Kadir Egilmez and M. Tayyar Kalcioglu

Department of Otorhinolaryngology, Faculty of Medicine, Istanbul Medeniyet University, 34722 Istanbul, Turkey

Correspondence should be addressed to M. Tayyar Kalcioglu; [email protected]

Received 14 December 2015; Accepted 19 January 2016

Academic Editor: Zhijun Duan

Copyright © 2016 O. K. Egilmez and M. T. Kalcioglu. This is an open access article distributed under the Creative CommonsAttribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work isproperly cited.

Congenital hearing impairment affects nearly 1 in every 1000 live births and is the most frequent birth defect in developed societies.Hereditary types of hearing loss account for more than 50% of all congenital sensorineural hearing loss cases and are caused bygenetic mutations. HL can be either nonsyndromic, which is restricted to the inner ear, or syndromic, a part of multiple anomaliesaffecting the body. Nonsyndromic HL can be categorised by mode of inheritance, such as autosomal dominant (called DFNA),autosomal recessive (DFNB), mitochondrial, and X-linked (DFN). To date, 125 deafness loci have been reported in the literature:58 DFNA loci, 63 DFNB loci, and 4 X-linked loci. Mutations in genes that control the adhesion of hair cells, intracellular transport,neurotransmitter release, ionic hemeostasis, and cytoskeleton of hair cells can lead to malfunctions of the cochlea and inner ear.In recent years, with the increase in studies about genes involved in congenital hearing loss, genetic counselling and treatmentoptions have emerged and increased in availability. This paper presents an overview of the currently known genes associated withnonsyndromic congenital hearing loss and mutations in the inner ear.

1. Introduction

Hearing loss (HL) is a common disorder, and congenitalhearing impairment affects nearly 1 in every 1000 live births; itis one of themost distressing disorders and themost frequentbirth defect in developed societies [1]. Hearing impairmentaffects speech development, language acquisition, and edu-cation in children and, as a result, often leads to decreasedopportunities in work life as those with hearing loss move toisolating themselves from society. In the US, it is estimatedthat the social costs of untreated hearing loss over the courseof a lifetime can reach up to $1.1 million for every untreatedperson [2].These costs could be decreased by 75 percent withearly intervention and treatment [3].

Hereditary hearing loss accounts for almost 50% of allcongenital sensorineural hearing loss cases, and it is causedby genetic mutations [4]. Deafness can be the result of amutation in a single gene or a combination of mutations ofdifferent genes; it can also be a result of environmental causessuch as trauma, medications, medical problems, and envi-ronmental exposure or the result of an association betweenenvironmental factors and genetics [5].

HL can be either nonsyndromic, which is restricted to theinner ear, or syndromic, a part ofmultiple anomalies affectingthe body. Nonsyndromic HL can further be categorised by itsmode of inheritance. Approximately 20% of nonsyndromicsensorineural hearing loss (NSSHL) is inherited as autosomaldominant, which is also referred to as DFNA; this typeof hearing loss is usually delayed onset. Eighty percentof inherited HL is autosomal recessive (DFNB), in whichhearing loss is generally congenital, but some forms mayemerge later in life. The inheritance of the remaining typesof HL is either mitochondrial or X-linked (DFN) (less than 1percent) [2]. To date, 125 deafness loci have been reported inthe literature: 58 DFNA loci, 63 DFNB loci, and 4 X-linkedloci (http://hereditaryhearingloss.org/) [6].

Many genes are involved in inner-ear function, and theear is very sensitive to mutations in genetic loci. This isbecause the physiology and structure of the inner ear areunique and unlike other anatomical locations. Mutations ingenes that control the adhesion of hair cells, intracellulartransport, neurotransmitter release, ionic hemeostasis, andcytoskeletons of hair cells can lead to malfunctions of thecochlea and inner ear.

Hindawi Publishing CorporationScientificaVolume 2016, Article ID 7576064, 9 pageshttp://dx.doi.org/10.1155/2016/7576064

2 Scientifica

In recent years, with the increase in studies of genesinvolved in congenital hearing loss, genetic counselling andtreatment options have emerged and increased in availability.In diagnostic tests, genes that are common causes of hearingloss, such asGJB2,GJB6, SLC26A4, andOTOF, are frequentlyinvolved [7].The results of these tests can be usedwhen coun-selling parents about the prognosis of a child’s hearing loss,predicting recurrence in the future offspring and taking intoconsideration therapeutic options like cochlear implantation[2]. In recent studies, some viral vectors were delivered intothe inner ear to replace the normal copy of the gene with thedefective gene causing hearing loss. In an animal study, anadenovirus-delivered SLC17A8 (VGLUT-3; vesicular gluta-mate transporter 3) was found to restore hearing in the mice.In another study, hair cell development and regenerationwereinduced by delivering the ATOH1 gene [8, 9].

Thisminireview has presented an overview and describedthe currently known genes associated with nonsyndromiccongenital hearing loss and mutations that cause malfunc-tional proteins in the inner ear (Table 1).

2. Genes and Proteins Related toNonsyndromic Hearing Loss

2.1. Adhesion Proteins. The stereocilia of hair cells in thecochlea are linked and interconnected to the tectorialmembrane by different adhesion proteins. Hair bundlesare stabilized by a set of temporary links such as transientlateral links and ankle links. These links also induce growthand maturation with signalling complexes [10]. In maturehair cells, stereocilia are connected by tectorial attachmentcrowns, horizontal top connectors, and tip links [2]. To date,several genes related to the linking apparatus have beenreported. These are DFNA4 (CEACAM16 (carcinogenicantigen-related cell adhesion molecule 16)) [11], DFNB12(CDH23 (cadherin 23)) [12], DFNB16 (STRC (stereocilin))[13], DFNB18 (USH1C (harmonin)) [14, 15], DFNB22 (OTOA(otoancorin)) [16], DFNB23 (PCDH15 (protocadherin 15))[17], DFNB31 (WHRN (whirlin)) [18], DFNB66/67 (TMHS(tetraspan membrane protein)) [19], and DFNB84 (PTPRQ(tyrosine phospate receptor Q)) [20].

The PTPRQ and TMHS genes, as well as cadherin 23and protocadherin 15, are parts of the transient laterallink. During development, they prevent the fusion of eachstereocilium themselves [2]. Inmature hair cells, they becomethe main parts of the tip link and act as a gate, channellingmechanotransduction and providing stability, taking a cen-tral role in auditory function [21].

Whirlin and harmonin regulate the link complexes andserve as scaffolding proteins. Mutations in these proteinscause autosomal recessive type hearing loss, but Sans,which isa third scaffolding protein, is related to a complex syndromichearing loss, Usher syndrome. The other genes, USH2𝛼 andVLGR1b, are also associated with Usher syndrome, and theyare part of the stereocilial ankle link [22].

Stereocilin is an extracellular matrix protein that attachesthe tallest stereocilia of the outer hair cells to the tecto-rial membrane [13]. The attachment site of this tectorial

membrane is generally formed by CEACAM16. In a similarway, otoancrin also attaches nonsensory cells to the tectorialmembrane [16].

2.2. Transport Proteins. In the inner ear, all parts of themyosin family can be used for the transportation of differentproteins. When using ATP, these myosin proteins bind to theactin cytockeleton and move forward. Binding sites for car-ried proteins are on the carboxyl-terminal tails of the trans-port proteins [23]. The myosins related to hereditary hearingloss are myosin Ia (DFNA48) [24], myosin IIIa (DFNB30)[25], myosin VI (DFNA22/DFNB37) [26, 27], myosin VIIa(DFNA11/DFNB2) [28, 29], nonmuscle myosin heavy chainIX (DFNA17) [30], nonmuscle myosin heavy chain XIV(DFNA4) [31], and myosin XVa (DFNB3) [32]. They all havetheir own unique functions in the inner-ear hair cells [2].

2.3. Proteins of Synapses. VGLUT3, which is a vesicularglutamate receptor, plays a role in the inner hair cells’synapses. It is encoded by SLC17A8 in the DFNA25 locusand related to autosomal recessive hearing loss [33]. Thisprotein regulates both the exocytosis and the endocytosis ofglutamate. Otoferlin (encoded by OTOF) is a protein thatworks with myosin VI at the synaptic cleft of the inner haircell and plays a role in the calcium-dependent fusion ofvesicles to the plasma membrane. As a result, glutamate isreleased and the afferent neuron is excited [34]. In an animalstudy with OTOF and SLC17A8 knockout mice, there was areduction in the number of postsynaptic ganglion cells, andit was concluded that these proteins are very important forthe preservation and development of normal hearing [35].

2.4. Electromotility. The cochlea is sensitive and selective tosounds delivered by the outer hair cells. This is introducedwith a process called electromotility, and a protein calledPrestin is thought to be responsible for this [2]. It changesthe membrane’s potential and enables the outer hair celllength to be altered. When this occurs, the outer hair cellbecomes longer upon hyperpolarization and shorter upondepolarization, so it amplifies its sensitivity to the sound [36].This protein is encoded as SLC26A5 and was first describedby Zheng et al. in 2000 [37]. Mutations in SLC26A5 are thecause of DFNB61 hearing loss [38].

2.5. Cytoskeleton. Mutations in some genes associated withthe organisation of the cytoskeleton can cause NSSHL;these are ESPN (espin), RDX (radixin), TRIOBP (trio-binding protein), ACTG1 (𝛾-actin), TPRN (taperin),DIAPH1(diaphanous), and SMPX (small muscle protein, X-linked).

The protein espin provides stability to the stereocilialcytoskeleton. A mutation in ESPN can cause DFNB36 andautosomal dominant hearing loss [39]. More steriocilliastability can be achieved with radixin. It links actin fil-aments to the plasma membrane and presents along thestereocilia. Mutations in RDX can cause DFNB24 and auto-somal recessive deafness [40]. 𝛾-actin acts as a buildingblock for the stereocilia of hair cells. These stereocilia areconstantly undergoing depolymerisation at the base and

Scientifica 3

Table1:Genes

related

with

nonsyn

drom

ichearingloss.

Locus

Gene

Chromosom

allocalization

Type

ofinheritance

Protein

Functio

nRe

ference

DFN

A1

DIAPH

15q31

AD

Diaph

anou

s1Ac

tinpo

lymerisa

tion(cytoskeleton)

[44]

DFN

A2A

KCNQ4

1p34

AD

KCNQ4

Voltage-gated

K+channel(ionhaem

ostasis)

[51]

DFN

A2B

GJB3(C

x31)

1p34

AD

Con

nexin31

Gap

junctio

n(io

nhaem

ostasis)

[57]

DFN

A3A

GJB2(C

x26)

13q12

AD

Con

nexin26

Gap

junctio

n(io

nhaem

ostasis)

[54]

DFN

A3B

GJB6(C

x30)

13q12

AD

Con

nexin30

Gap

junctio

n(io

nhaem

ostasis)

[55]

DFN

A4

MYH

1419q13

AD

Non

muscle

myosin

heavychainXIV

Transport

[31]

DFN

A4

CAEC

AM16

19q13

AD

Carcinogenicantig

en-rela

tedcell

adhesio

nmolecule16

TMattachmentcrown(adh

esion)

[11]

DFN

A8/12

TECT

A11q22-24

AD

A-tectorin

Stabilityandstr

ucture

ofTM

(ECM

)[28]

DFN

A9

COCH

14q12-q13

AD

Cochlin

Structureo

fspirallim

bus

[30]

DFN

A10

EYA4

6q22-q23

AD

Eyes

absent

4Re

gulatio

nof

transcrip

tion(tr

anscrip

tionfactor)

[42]

DFN

A11

MYO

7A11q12.3-q21

AD

Myosin

VIIa

Transport

[43]

DFN

A13

COLL

11A2

6p21

AD

Type

XIcollagen𝛼2

Stabilityandstr

ucture

ofTM

(ECM

)[26]

DFN

A15

POU3F4

5q31

AD

Class3

POU

Regu

latio

nof

transcrip

tion(tr

anscrip

tionfactor)

[33]

DFN

A17

MYH

922q

AD

Non

muscle

myosin

heavychainIX

Transport

[24]

DFN

A20/26

ACTG

117q25

AD

𝛾-actin

Build

ingcytoskeleton

(cytoskeleton)

[50,56]

DFN

A22

MYO

66q

13AD

Myosin

VI

Regu

latio

nof

exocytosis,

anchoringste

reocilia

(cytoskeleton)

[29]

DFN

A25

SLC17A

812q21-2

4AD

VGLU

T-3

Regu

latio

nof

exocytosisandendo

cytosis

ofglutam

ate

(transport)

[32]

DFN

A28

TFCP

2L3

8q22

AD

Transcrip

tionfactor

CP2-lik

e3Re

gulationof

transcrip

tion(tr

anscrip

tionfactor)

[52]

DFN

A48

MYO

1A12q13-q14

AD

Myosin

IaTransport

[34]

DFN

A50

MIR96

7q32

AD

MicroRN

A96

Regu

latio

nof

transcrip

tion(tr

anscrip

tionfactor)

[12]

DFN

A51

TJP2

AD

Tightjun

ctionprotein2

Cellcyclesig

nalin

g,bind

ingtig

htjunctio

nsto

mem

brane

[13]

DFN

A56

TNC

9q31.3-q34.3

AD

Tenascin-C

Stabilityandstr

ucture

ofTM

(ECM

)[14

]

DFN

A64

SMAC

/DIABL

O12q24.31-

12q24.32

AD

Second

Mito

chon

dria-D

erived

Activ

ator

ofCa

spase/Dire

ctInhibitoro

fAp

optosis

proteinBind

ingproteinwith

alow

pI

Cellcyclesig

nalin

g[15]

DFN

A65

TBC1

D24

16p13.3

AD

Tbc1do

mainfamily,m

ember2

4En

coding

aGTP

ase-activ

atingproteinexpressedin

the

cochlea

[16,17]

DFN

A67

OSB

PL2

20q13.2-q13.33

AD

Oxyste

rol-b

inding

Protein-lik

eProtein

2Intracellulartranspo

rtof

lipids,particularlyoxysterol

(transport)

[40,45]

HOMER

215q25.2

AD

Hom

er,drosoph

ila,hom

olog

of2

Negativer

egulator

ofTcellactiv

ation

[46]

DFN

B1A

GJB2(C

x26)

13q11-q

12AR

Con

nexin26

Gap

junctio

n(io

nhaem

ostasis)

[13]

DFN

B1B

GJB6(C

x30)

13q12

AR

Con

nexin30

Gap

junctio

n(io

nhaem

ostasis)

[49]

4 Scientifica

Table1:Con

tinued.

Locus

Gene

Chromosom

allocalization

Type

ofinheritance

Protein

Functio

nRe

ference

DFN

B2MYO

7A11q

AR

Myosin

VIIa

Transport

[25,43]

DFN

B3MYO

15A

17p11.2

AR

Myosin

Xva

Transport

[18]

DFN

B4SLC2

6A4

7q31

AR

Pend

rinAc

id-baseb

alance

ofendo

lymph

(ionhaem

ostasis)

[39]

DFN

B9OTO

F2p23-p22

AR

Otoferlin

Fusio

nof

synapticvesic

lesw

ithCa+2(tr

ansport)

[38]

DFN

B12

CDH23

10q21-q

22AR

Cadh

erin

23Lateraland

tiplin

k(adh

esion)

[19]

Mod

ifier

ofDNFB

12AT

P2b2/PMCA

21p32.3

AR

ATP2

b2AT

Pdepend

entC

a+2pu

mp

[53]

DFN

B16

STRC

15q15

AR

Stereocilin

TMattachmentlinks

(adh

esion)

[20]

DFN

B18

USH

1C11p15.1

AR

Harmon

inScaffolding

protein(adh

esion)

[48,58]

DFN

B21

TECT

A11q22-q24

AR

𝛼-te

ctorin

Stabilityandstr

ucture

ofTM

(ECM

)[10]

DFN

B22

OTO

A16p12.2

AR

Otoancorin

TMattachmenttono

nsensroy

cells

(adh

esion)

[21]

DFN

B23

PCDH15

10q21-q

22AR

Protocadherin

15Lateraland

tiplin

k(adh

esion)

[22]

DFN

B24

RDX

11q23

AR

Radixin

Actin

bind

ingto

plasmam

embrane(cytoskeleton

)[23]

DFN

B28

TRIO

BP22q13.1

AR

Trio-binding

protein

Actin

bind

ingandorganisatio

n(cytoskeleton)

[27,35]

DFN

B29

CLDN14

21q22.3

AR

Claudin14

Tightjun

ction(io

nhaem

ostasis)

[36]

DFN

B30

MYO

3A10p11.1

AR

Myosin

IIIa

Transport

[37]

DFN

B31

WHRN

9q32-q34

AR

Whirlin

Scaffolding

protein(adh

esion)

[41]

DFN

B35

ESRR

B14q21.1-q24.3

AR

Oestro

gen-related

receptor𝛽

Regu

latio

nof

transcrip

tion(tr

anscrip

tionfactor)

[47]

DFN

B36

ESPN

1p36.3-p36.1

AR

Espin

Actin

crosslink

ingandbu

ndlin

g(cytoskeleton)

[59]

DFN

B37

MYO

66q

13AR

Myosin

VI

Regu

latio

nof

exocytosis,

stereociliaa

ncho

ring(tr

ansport)

[60]

DFN

B49

TRIC

5q12.3-q14.1

AR

Tricellulin

Tightjun

ction(io

nhaem

ostasis)

[53]

DFN

B53

COL11A

26p

21.3

AR

Type

XIcollagen𝛼2

Stabilityandstr

ucture

ofTM

(ECM

)[61]

DFN

B61

SLC2

6A5

AR

Prestin

Electro

motility

[62]

DFN

B67

TMHS

6p21.3

AR

Tetraspanmem

branep

rotein

Transie

ntlin

k(adh

esion)

[63]

DFN

B73

BSND

AR

Barttin

K+channelm

aturationandtraffi

cking(io

nhaem

ostasis)

[64]

DFN

B79

TPRN

9q34.3

AR

Taperin

Actin

regu

lation(cytoskeleton)

[65]

DFN

B84

PTPR

Q12q21.3

1-q21.2

AR

Proteintyrosin

epho

sphatereceptor

QTransie

ntlin

k(adh

esion)

[66]

DFN

B91

GJB3

6p25

AR

Con

nexin31

Gap

junctio

n(io

nhaem

ostasis)

[67]

DFN

B93

CABP

211q

13.2

AR

Calcium

-binding

protein2

(ionhaem

ostasis)

[68]

DFN

B94

NARS

211q14.1

AR

Asparaginyl-tR

NAsynthetase

2(tr

ansport)

[69]

DFN

B97

MET

7q31.2

AR

MET

protoo

ncogene

Cell-surface

receptor

forh

epatocyteg

rowth

factor

(adh

esion)

[70]

DFN

B98

TSPE

AR

21q22.3

AR

Thrombo

spon

din-type

laminin

gdo

mainandearrepeats

Cellp

ermeabilization(tr

ansport)

[71]

DFN

B99

TMEM

132E

17q12

AR

Transm

embranep

rotein

132e

Extracellularreceptor

[72]

DFN

B101

GRX

CR2

5q32

AR

Glutaredo

xin,

cyste

ine-ric

h2

Organisa

tionof

stereocilia(

adhesio

n)[73]

DFN

B102

EPS8

12p12.3

AR

Epidermalgrow

thfactor

receptor

pathway

substrate8

Regu

latin

gRa

c-specificG

EFactiv

ity(tr

anscrip

tionfactor)

[74]

Scientifica 5

Table1:Con

tinued.

Locus

Gene

Chromosom

allocalization

Type

ofinheritance

Protein

Functio

nRe

ference

DFN

B103

CLIC5

6p21.1

AR

Chlorid

eintracellu

larc

hann

el5

(ionhaem

ostasis)

[75]

FAM65B

6p22.3

AR

Family

with

sequ

ence

similarity65,

mem

berb

(Cytoskleton

)[76]

Usher

synd

rome

SANS/USH

1G17q24-25

AR

SANS

Scaffolding

protein(adh

esion)

[77]

Usher

synd

rome

USH

2A1q41

AR

Usherin

Ank

lelin

k(adh

esion)

[78]

Usher

synd

rome

VLG

R1B

AR

Very

largeG

protein-coup

ledreceptor

1Ank

lelin

k(adh

esion)

[79]

DFN

2PR

PS1

Xq22.3

X-lin

ked

Phosph

oribosylpyroph

osph

ate

synthetase

1Pu

rinea

ndpyrim

idineb

iosynthesis

[80]

DFN

3PO

U3F4

Xq21

X-lin

ked

Class3

POU

Regu

lationof

transcrip

tion(tr

anscrip

tionfactor)

[81]

DFN

6SM

PXXp

21.2

X-lin

ked

Smallm

uscle

proteinX-

linked

Stereociliald

evelop

mentand

maintenance

(cytoskeleton)

[82]

DFN

X6CO

L4A6

Xq22.3

X-lin

ked

Collagen,

type

IV,alpha-6

Stabilityandstr

ucture

ofTM

(ECM

)[83]

DFN

A=no

nsyn

drom

icdeafness,autosom

aldo

minant;DFN

B=no

nsyn

drom

icdeafness,autosom

alrecessive;AD=autosomaldo

minant;AR=autosomalrecessive;TM

=tectorialm

embrane;EC

M=extracellular

matrix

;Ca+2

=calcium

ion;

K+=po

tassium

ion.

6 Scientifica

actin polymerisation at the tip [41]. Mutations in ACTG1can cause DFNA20/26 and autosomal dominant hearing loss[42, 43]. Via a constant remodelling process, other proteinsare also important for continuity. Diaphanous 1 regulates thereorganisation and polymerisation of actin monomers intopolymers. It is encoded as DIAPH1, and mutations in thisgene can cause DFNA1 and autosomal dominant hearing loss[44]. The binding and organisation of 𝛾-actin at the base ofstereocilia are provided by two isoforms of the TRIOBP gene.Mutations in isoforms that are TRIOBP4 and TRIOBP5 cancause DFNB28 and autosomal recessive type hearing loss [45,46]. Another protein, taperin, is localised in the base of thestereocilia and associated with DFNB79 [47]. Small muscleprotein X-linked, encoded as SMPX (DFN4), has a functionin stereocilial development and maintenance in response tothe mechanical stress to which stereocilia are subjected [48].

2.6. Ion Homeostasis and Gap Junctions. The cochlea hastwo types of fluids: perilymph, which is high in sodiumand low in potassium, and endolymph, which is high inpotassium and low in sodium; this condition makes a highlypositive potential (+80mV) called endocochlear potential.Potassium influx into the hair cells causes depolarisationand, after that, the hair cell repolarises and moves cationsback into the endolymph.This ion homeostasis involves tightjunction protein 2 (TJP2), tricellulin (MARVELD2/TRIC),claudin 14 (CLDN14), KCNQ4 (KCNQ4), Barttin (BSND),ATP2b2 (ATP2b2/PMCA2), some connexins (GJBs), andpendrin (SLC26A4), and they are all related to hereditaryhearing loss [2].

In a mutation of CLDN14 in DFNB29, claudin 14 proteinwill be absent or dysfunctional, and the space of Nuel thatsurrounds the basolateral surface of outer hair cells is affectedand might change its electrical potential [49]. Similarly,tricellulin, which is encoded as MARVELD2/TRIC, causesDFNB49whenmutated, and it is functioning as tight junctionthat connects the cells together [45]. Tight junction protein 2,encoded as the TJP2 gene, binds tight junctions to the actincytoskeleton, and mutations cause DFNA51 and autosomaldominant type hearing loss [50].

KCNQ4 encodes a protein forming a voltage-gated potas-sium channel. It is expressed in outer hair cells and, ifmutated, causes an autosomal dominant type HL, DFNA2a[51]. It aids in the repolarisation of outer hair cells andregulates the sensitivity to sound.

Barttin and pendrin, encoded as BSND and SLC26A4,respectively, are involved in both nonsyndromic and syn-dromicHL. Pendrin is an anion exchanger and plays a crucialrole in the acid-base balance. Both syndromic (Pendred’ssyndrome, associated with goiter) and nonsyndromic HL(DFNB4) are related to the extent of themutation in SLC26A4[52]. Barttin protein is one of the subunits of the chloridechannel. Mostly, mutations in BSND can cause Bartter syn-drome, associated with hearing loss and renal abnormalities,but DFNB73 has also been attributed to a mutation in BSNDand causing nonsyndromic deafness [53].

A gap junction is a channel extending over two adjacentmembranes that enables the exchange of various moleculesand ions in the cochlea. These junctions are made up of

proteins called connexins. These junctions also play a role inthe recycling of potassium ions needed for normal hearing.it is the most common cause of nonsyndromic HL and wasthe first identified gene is GJB2; it is encoded as connexin26 (DFNA3a/DFNB1a) [54]. Other connexins related to non-syndromic HL are connexin 30 (GJB6, DFNA3b/DFNB1b)[55, 56] and connexin 31 (GJB3, DFNA2b/DFNB91) [57, 58].

2.7. Others. There are also extracellular matrix proteins, thatis, TECTA (𝛼-tectorin), COL11A2 (type XI collagen 𝛼2), andCOCH (cochlin), and transcription factors, such as POU4f3(class 4 POU), POU3f4 (class 3 POU), MIR96 (microRNA96), GRHL2 (grainy-head-like 2), ESRRB (oestrogen-relatedreceptor 𝛽), and EYA4 (eyes absent 4) involved in hereditaryHL.

3. Conclusion

This review presents an overview and description of thecurrently known genes related to hereditary NSSHL. Thefunctions of these genes will be better understood with time,and more genes leading to hearing loss will be discoveredsoon. With new studies and continued examination, thefunction of the cochlea will be better understood, and novelmolecular and gene therapies for human sensorineural HLwill hopefully be developed.

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper.

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